WO2013102860A1 - Therapeutic use of imidazopyridine derivatives - Google Patents

Therapeutic use of imidazopyridine derivatives Download PDF

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Publication number
WO2013102860A1
WO2013102860A1 PCT/IB2013/050048 IB2013050048W WO2013102860A1 WO 2013102860 A1 WO2013102860 A1 WO 2013102860A1 IB 2013050048 W IB2013050048 W IB 2013050048W WO 2013102860 A1 WO2013102860 A1 WO 2013102860A1
Authority
WO
WIPO (PCT)
Prior art keywords
alk
group
carbonyl
alkyl
pyridin
Prior art date
Application number
PCT/IB2013/050048
Other languages
English (en)
French (fr)
Inventor
Chantal Alcouffe
Corentin Herbert
Original Assignee
Sanofi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=47630451&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2013102860(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AU2013207082A priority Critical patent/AU2013207082B2/en
Priority to ES13702101.0T priority patent/ES2560619T3/es
Priority to BR112014016632A priority patent/BR112014016632A8/pt
Priority to SG11201403793UA priority patent/SG11201403793UA/en
Priority to US14/370,462 priority patent/US9732078B2/en
Priority to EP13702101.0A priority patent/EP2800566B1/en
Priority to MX2014008244A priority patent/MX336340B/es
Application filed by Sanofi filed Critical Sanofi
Priority to EA201491307A priority patent/EA027058B1/ru
Priority to CA2860413A priority patent/CA2860413C/en
Priority to PL13702101T priority patent/PL2800566T3/pl
Priority to KR1020147021454A priority patent/KR102046196B1/ko
Priority to CN201380012217.8A priority patent/CN104144687B/zh
Priority to JP2014550790A priority patent/JP6067032B2/ja
Publication of WO2013102860A1 publication Critical patent/WO2013102860A1/en
Priority to IL233493A priority patent/IL233493A/en
Priority to PH12014501537A priority patent/PH12014501537A1/en
Priority to ZA2014/04928A priority patent/ZA201404928B/en
Priority to MA37231A priority patent/MA35878B1/fr
Priority to HK14112128.4A priority patent/HK1198690A1/xx

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • R c represents a hydrogen atom or -CO-NR 5 R 6 ,
  • a fourth subgroup which is a subject of the invention is the use of a compound of formula (I) in which R 2 and R 3 together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to one of the formulae (A) and (B) defined above, preferably corresponding to formula (A),
  • R a represents a hydrogen atom or an alkyl group, optionally substituted with one or more halogens, -AlkCONR 5 R 6 , haloalkyl, -CH 2 -COOR 5 , -Alk-heteroaryl, - Alk-O-phenyl or -Alk-phenyl, where the phenyl group is optionally substituted with one or two alkyl and/or OR 5 groups and/or halogen atoms; -Alk-cycloalkyl, .
  • R a ' represents a hydrogen atom or a linear, branched, cyclic or partially cyclic alkyl group, or a -CH 2 -OR 5 or -Alk-NR 5 R 6 group,
  • R a ' represents a hydrogen atom or a linear, branched, cyclic or partially cyclic alkyl group or an -Alk-OR 5 or -Alk-NR 7 R 8 group, Ra' being optionally substituted with one or more halogen atoms,
  • the compound (VIII) is subjected to a saponification reaction in order to obtain the compound (XXIV).
  • the compound (XXIV) is subjected to a condensation reaction with an alkyl or aryl anhydride (R b 'CO) 2 0 in order to obtain the compound of formula (XVII).
  • the compound of formula (XVI I) is subjected to a condensation reaction with an amine R b NH 2 in order to obtain a compound of formula (I) in which R b and R b ' are defined as previously.
  • the compound (X) is subjected to a saponification reaction in order to obtain the compound (XIX).
  • the compound (XIX) is subjected to a condensation reaction in the presence of triphosgene in order to obtain the compound (XX).
  • the compound (XX) is subjected to an alkylation reaction in the presence of a halogenated derivative R C "X or of a protective group in order to obtain the compound (XXI).
  • the compound (XXI) is subjected to a condensation reaction with a malonic derivative in order to obtain the compound (XXII) in which R c > et R c are defined as previously.
  • the compound (XXII) is subjected, in the presence of a palladium catalyst, of a ligand and of a base,
  • the reaction medium is acidified with an aqueous 1 N hydrochloric acid solution, and extracted with dichloromethane.
  • the organic phase is washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • the residue obtained is placed in solution in 5 ml of DMF.
  • 30 ⁇ (0.5 mmol) of methyl iodide and 0.052 g (0.16 mmol) of caesium carbonate are added.
  • the reaction medium is hydrolysed with water and then extracted with ethyl acetate.
  • the organic phase is dried over sodium sulphate, filtered and then concentrated under reduced pressure.
  • the solid obtained is taken up in methanol. After filtration and drying overnight at 50°C under reduced pressure, 0.379 g of a yellow solid is obtained.
  • the product obtained is dissolved in 60 ml of an NMP. 3.59 g (6.4 mmol) of potassium hydroxide dissolved in 1 1 ml of water are added. The reaction medium is heated at 100°C for 8 hours and then poured onto an aqueous 1 N hydrochloric acid solution. After filtration, the solid obtained is rinsed with water and then dried overnight in an incubator under reduced pressure at 40°C. 5.45 g of a yellow solid are obtained.
  • Example 10 N-[2-(dimethylamino)ethyl]-3-(3- ⁇ [3-(4-fluorobenzyl)-1 -methyl-2,4- dioxo-1 ,2,3,4-tetrahydroquinazolin-6-yl]carbonyl ⁇ imidazo[1 ,5-a]pyridin-1 - yl)benzamide hydrochloride (compound No.116) 0.06 ml (0.55 mmol) of N,N-dimethylethylenediamine, 0.134 g (0.41 mmol) of TOTU and 0.14 ml (0.82 mmol) of diisopropylethylamine are added to 0.15 g (0.27 mmol) of 3-(3- ⁇ [3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6- yl]carbonyl ⁇ imidazo[1 ,5-
  • the residue obtained is washed with 100 ml of water and then dried under reduced pressure at 40°C overnight.
  • the solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (75/1 ) mixture. 0.55 g of a yellow solid is obtained.
  • Example 18 Evaluation of the capacity of the FGF-R antagonists to reduce the ATP content of TCC97-7 bladder cancer cells carrying the Ser249Cys mutation of FGF receptor 3, cultured in a serum-supplemented medium
  • the percentage inhibition of the amount of intracellular ATP is calculated by considering the ATP content of the cells cultured in the absence of antagonist to be 0% inhibition. 100% inhibition would correspond to a well in which the ATP content is zero.
  • the compounds of the present invention are considered to be active from the moment an inhibition of greater than or equal to 20% at the dose of less than or equal to 30 ⁇ is observed.
  • compounds 29, 49, 55, 71 , 79, 1 12, 1 16, 148, 207, 220, 291 , 221 , 224, 226, 232 and 240 are capable of inhibiting the amount of intracellular ATP in the TCC97-7 cells by more than 20% at the doses of 1 , 10 or 30 ⁇ (Table No. 3).
  • the medium is drawn off, the cells are rinsed with cold PBS and 80 ⁇ of RIPA buffer (Sigma, R0278) containing a cocktail of protease and phosphatase inhibitors (Pierce, 78440) is added to each well at 4°C for 30 min.
  • the protein lysates are then collected and centrifuged at 13 000 rpm, at 4°C, for 10 min. The supernatants are then separated by acrylamide gel electrophoresis (4-20%).
  • the present invention relates to the use of pharmaceutical compositions comprising, as active ingredient, a compound of formula (I) for the treatment of bladder cancer.
  • pharmaceutical compositions contain an effective dose of at least one compound according to formula (I), or a pharmaceutically acceptable salt, and also at least one pharmaceutically acceptable excipient, used for the treatment of bladder cancer.
  • excipients are chosen, according to the pharmaceutical form and the mode of administration desired, from the usual excipients which are known to those skilled in the art.
  • the active ingredient of formula (I) above, or its optional salt, solvate or hydrate can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals or to human beings for the prophylaxis or treatment of the abovementioned disorders or diseases.
  • the appropriate unit administration forms include oral forms, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular, intravesical or intravenous administration forms, rectal administration forms, and implants.
  • oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
  • sublingual, buccal, intratracheal intraocular and intranasal administration forms, forms of administration by inhalation
  • topical transdermal
  • subcutaneous intramuscular
  • intravesical or intravenous administration forms rectal administration forms
  • implants implants.
  • the compounds according to formula (I) can be used in creams, gels, ointments or lotions.
  • a unit administration form of a compound according to the invention tablet form may comprise the following constituents: FGF receptor inhibitor compound 50.0 mg
  • the present invention also relates to a pharmaceutical composition as defined above, as a medicament for the treatment of bladder cancer.
  • a compound of formula (I) according to the use of the present invention can be administered alone or in combination with one or more compound(s) having an anti- angiogenic activity or with one or more cytotoxic compound(s) (chemotherapy), or else in combination with a radiation treatment.
  • chemotherapy cytotoxic compound(s)
  • a subject of the present invention is also the use of a compound of formula (I), as defined above, in combination with one or more anticancer active ingredient(s) and/or with radiotherapy.
  • compositions according to the invention for oral administration, contain recommended doses of from 0.01 to 700 mg. There may be particular cases where higher or lower dosages are appropriate; such dosages do not depart from the context of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the age, weight and response of the patient, and also according to the degree of progression of the disease. According to another of its aspects, the present invention also relates to a method for treating bladder cancer, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/IB2013/050048 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives WO2013102860A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
EA201491307A EA027058B1 (ru) 2012-01-04 2013-01-03 Терапевтическое применение имидазопиридиновых производных соединений
JP2014550790A JP6067032B2 (ja) 2012-01-04 2013-01-03 イミダゾピリジン誘導体の治療的使用
BR112014016632A BR112014016632A8 (pt) 2012-01-04 2013-01-03 uso terapêutico de derivados de imidazopiridina
SG11201403793UA SG11201403793UA (en) 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives
US14/370,462 US9732078B2 (en) 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives
EP13702101.0A EP2800566B1 (en) 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives
MX2014008244A MX336340B (es) 2012-01-04 2013-01-03 Utilizacion en terapeutica de derivados de imidazopiridina.
PL13702101T PL2800566T3 (pl) 2012-01-04 2013-01-03 Zastosowanie terapeutyczne pochodnych imidazopirydyny
CA2860413A CA2860413C (en) 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives
AU2013207082A AU2013207082B2 (en) 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives
ES13702101.0T ES2560619T3 (es) 2012-01-04 2013-01-03 Uso terapéutico de derivados de imidazopiridina
KR1020147021454A KR102046196B1 (ko) 2012-01-04 2013-01-03 이미다조피리딘 유도체의 치료적 용도
CN201380012217.8A CN104144687B (zh) 2012-01-04 2013-01-03 咪唑并吡啶衍生物的治疗用途
IL233493A IL233493A (en) 2012-01-04 2014-07-02 Imidazopyridine derivatives for cancer treatment
PH12014501537A PH12014501537A1 (en) 2012-01-04 2014-07-03 Therapeutic use of imidazopyridine derivatives
ZA2014/04928A ZA201404928B (en) 2012-01-04 2014-07-04 Therapeutic use of imidazopyridine derivatives
MA37231A MA35878B1 (fr) 2012-01-04 2014-07-23 Utilisation thérapeutique de dérivés d'imidazopyridine
HK14112128.4A HK1198690A1 (en) 2012-01-04 2014-12-02 Therapeutic use of imidazopyridine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1250075A FR2985185B1 (fr) 2012-01-04 2012-01-04 Utilisation en therapeutique de derives d'imidazopyridine
FR1250075 2012-01-04

Publications (1)

Publication Number Publication Date
WO2013102860A1 true WO2013102860A1 (en) 2013-07-11

Family

ID=47630451

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2013/050048 WO2013102860A1 (en) 2012-01-04 2013-01-03 Therapeutic use of imidazopyridine derivatives

Country Status (24)

Country Link
US (1) US9732078B2 (ru)
EP (1) EP2800566B1 (ru)
JP (1) JP6067032B2 (ru)
KR (1) KR102046196B1 (ru)
CN (1) CN104144687B (ru)
AU (1) AU2013207082B2 (ru)
BR (1) BR112014016632A8 (ru)
CA (1) CA2860413C (ru)
CL (1) CL2014001784A1 (ru)
CO (1) CO7020916A2 (ru)
EA (1) EA027058B1 (ru)
ES (1) ES2560619T3 (ru)
FR (1) FR2985185B1 (ru)
HK (1) HK1198690A1 (ru)
IL (1) IL233493A (ru)
MA (1) MA35878B1 (ru)
MX (1) MX336340B (ru)
PH (1) PH12014501537A1 (ru)
PL (1) PL2800566T3 (ru)
SG (1) SG11201403793UA (ru)
TW (1) TWI557122B (ru)
UY (1) UY34564A (ru)
WO (1) WO2013102860A1 (ru)
ZA (1) ZA201404928B (ru)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3601264A4 (en) * 2017-03-22 2021-03-24 Xibin Liao INHIBITORS OF BRUTON TYROSIN KINASE

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115490687B (zh) * 2022-09-19 2023-10-27 国家烟草质量监督检验中心 3-苯并呋喃基硫咪唑并吡啶衍生物及其制备方法和应用

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Publication number Priority date Publication date Assignee Title
WO2005028476A1 (fr) 2003-09-18 2005-03-31 Sanofi-Aventis Derives d'indolizine 1,2,3,6,7,8 substituee, inhibiteurs des fgfs, leur procede de preparation et les compositions pharmaceutiques les contenant
WO2006097625A1 (fr) 2005-03-16 2006-09-21 Sanofi-Aventis NOUVEAUX DÉRIVÉS D'IMIDAZO[1,5-a]PYRIDINES, LEUR PROCÉDÉ DE PRÉPARATION ET LES COMPOSITIONS PHARMACEUTIQUES LES CONTENANT.
WO2007080325A1 (fr) * 2006-01-13 2007-07-19 Sanofi-Aventis Composes dimeres agonistes des recepteurs des fgfs
WO2012004732A1 (en) * 2010-07-06 2012-01-12 Sanofi Imidazopyridine derivatives, process for the preparation thereof and therapeutic use thereof

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
EP1891955A1 (en) 2006-07-24 2008-02-27 Sanofi-Aventis Use of 1,2,3-substituted indolizine derivatives, inhibitors of FGFs, for the preparation of a medicament intended for the treatment of degenerative joint diseases
CN1887878A (zh) 2006-07-26 2007-01-03 浙江大学 三嗪氮氧化物及合成方法和用途

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Publication number Priority date Publication date Assignee Title
WO2005028476A1 (fr) 2003-09-18 2005-03-31 Sanofi-Aventis Derives d'indolizine 1,2,3,6,7,8 substituee, inhibiteurs des fgfs, leur procede de preparation et les compositions pharmaceutiques les contenant
WO2006097625A1 (fr) 2005-03-16 2006-09-21 Sanofi-Aventis NOUVEAUX DÉRIVÉS D'IMIDAZO[1,5-a]PYRIDINES, LEUR PROCÉDÉ DE PRÉPARATION ET LES COMPOSITIONS PHARMACEUTIQUES LES CONTENANT.
WO2007080325A1 (fr) * 2006-01-13 2007-07-19 Sanofi-Aventis Composes dimeres agonistes des recepteurs des fgfs
WO2012004732A1 (en) * 2010-07-06 2012-01-12 Sanofi Imidazopyridine derivatives, process for the preparation thereof and therapeutic use thereof

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GREEN ET AL.: "Protective Groups in Organic Synthesis", JOHN WILEY & SONS, INC.
J. CHEM. SOC., 1955, pages 2834 - 2836
J. MARCH: "Advances in Organic Chemistry", WILEY INTERSCIENCE, pages: 310 - 316
LAMONT F R ET AL: "Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo", BRITISH JOURNAL OF CANCER, vol. 104, no. 1, January 2011 (2011-01-01), pages 75 - 82, XP002683505, ISSN: 0007-0920 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3601264A4 (en) * 2017-03-22 2021-03-24 Xibin Liao INHIBITORS OF BRUTON TYROSIN KINASE
AU2018237123B2 (en) * 2017-03-22 2022-08-04 Xibin Liao Bruton's tyrosine kinase inhibitors
US11554118B2 (en) 2017-03-22 2023-01-17 Xibin Liao Bruton's tyrosine kinase inhibitors
IL269152B1 (en) * 2017-03-22 2023-07-01 Liao Xibin Broughton's kinase designers

Also Published As

Publication number Publication date
CA2860413C (en) 2020-02-25
BR112014016632A8 (pt) 2017-07-04
ES2560619T3 (es) 2016-02-22
CA2860413A1 (en) 2013-07-11
SG11201403793UA (en) 2014-08-28
ZA201404928B (en) 2015-10-28
KR102046196B1 (ko) 2019-11-18
CN104144687B (zh) 2017-09-05
PH12014501537A1 (en) 2014-10-08
EP2800566B1 (en) 2015-10-28
MX2014008244A (es) 2014-11-25
AU2013207082B2 (en) 2017-06-15
CN104144687A (zh) 2014-11-12
EA027058B1 (ru) 2017-06-30
KR20140107667A (ko) 2014-09-04
IL233493A0 (en) 2014-08-31
EA201491307A1 (ru) 2014-11-28
UY34564A (es) 2013-09-02
IL233493A (en) 2017-02-28
FR2985185A1 (fr) 2013-07-05
TW201333008A (zh) 2013-08-16
US9732078B2 (en) 2017-08-15
MA35878B1 (fr) 2014-12-01
AU2013207082A1 (en) 2014-07-31
BR112014016632A2 (pt) 2017-06-13
TWI557122B (zh) 2016-11-11
CO7020916A2 (es) 2014-08-11
PL2800566T3 (pl) 2016-04-29
US20140343054A1 (en) 2014-11-20
MX336340B (es) 2016-01-15
FR2985185B1 (fr) 2013-12-27
HK1198690A1 (en) 2015-05-29
JP2015505311A (ja) 2015-02-19
CL2014001784A1 (es) 2014-10-17
EP2800566A1 (en) 2014-11-12
JP6067032B2 (ja) 2017-01-25

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